Pharmacokinetic-pharmacodynamic analysis of vismodegib in patients with basal cell carcinoma (the OPTIVISMO study)

WHAT IS KNOWN AND OBJECTIVEVismodegib is indicated in patients with symptomatic metastatic basal cell carcinoma (BCC) or locally advanced BCC when surgery or radiotherapy are not appropriate. The significant efficacy of vismodegib in responding patients and lack of therapeutic alternatives are counterbalanced by intolerance and severe adverse events (AEs), leading to discontinuation in 30% of patients. We aimed to evaluate the relationship between vismodegib pharmacokinetics (PK) and occurrence of AEs, and to investigate the association between concentrations and response in terms of efficacy. RESULTSMean of trough vismodegib plasma concentrations ranged from 3.9 mg/L to 30 mg/L per patient, with an overall mean of 11.8 ({+/-} 5) mg/L. A high correlation between total vismodegib and alpha-1 acid glycoprotein (AAG) levels was observed (Spearmans {rho} = 0.6733, p-value =1.662e-12). Inter-individual variability was significant (CV% of 42%). Patients with stable and progressive disease had a significantly higher median vismodegib plasma concentration than those with partial and complete response (p = 0.03). Tumor volume ranged from 0 to 12 292 135 mm3 in our cohort. Mean tumor volume slope was -1187.97 ({+/-} 9734). WHAT IS KNEW AND CONCLUSIONWe explored PK/pharmacodynamic (PD) relationships of vismodegib in patients with BCC. This is the first study which reported PK data obtained in BCC patients treated with vismodegib in a real-life clinical practice. Our study confirmed the strong influence of AAG levels on vismodegib protein binding. Concerning the PK/PD relationship evaluation, we notably observed that patients with the lowest plasma concentrations respond best to treatment. Our mathematical estimation of tumor volume showed that between the beginning and the end of the study, tumor growth was positively correlated to vismodegib levels, which was in line with the correlation observed for efficacy/safety data.